The present invention relates to topically administrable ophthalmic and otic pharmaceutical compositions. In particular, this invention relates to a process for manufacturing compositions comprising ciprofloxacin, hydrocortisone and lecithin.
U.S. Pat. No. 5,843,930 discloses topically administrable ophthalmic and otic compositions comprising (a) ciprofloxacin in aqueous solution in an amount effective for antibacterial action; (b) a non-ionic viscosity augmenter unaffected by pH and ionic level, said viscosity augmenter being present in an amount effective for augmenting the viscosity of the composition to a viscosity greater than that of water, said viscosity augmenter being at least 85% hydrolyzed polyvinyl alcohol; (c) a non-ototoxic preservative present in an amount effective for antibacterial action the preservative being benzyl alcohol; (d) water sufficient to produce an aqueous composition; (e) hydrocortisone in aqueous suspension in an amount effective for anti-inflammatory action; (f) lecithin in an amount effective for enhancing suspension of other constituents in the compositions; and (g) polysorbate ranging from polysorbate 20 to 80 in an amount effective for spreading the preparation on a hydrophobic skin surface to the site of infection or inflammation.
According to the ""930 patent, the compositions comprising ciprofloxacin and hydrocortisone contain polyvinyl alcohol in an amount effective for augmenting the viscosity of the composition to a viscosity greater than that of water and suspending other constituents of the composition. To allow a ciprofloxacin preparation to be administered in drops from a medicine dropper and to flow by gravity to and remain or deposit in an effective amount at a selected area, a viscosity-augmenting agent that would also serve to suspend hydrocortisone was desirable. For compatibility with ciprofloxacin hydrochloride solubility, viscosity-augmenting agents were preferably non-ionic and unaffected by pH and ionic level. See Col., 8, lines 13-31 of the ""930 patent.
Polyvinyl alcohol was selected for its ability to produce a suitable viscosity and a high ability to suspend hydrocortisone in aqueous preparations. See the ""930 patent at Col. 8, lines 32-37. The addition of lecithin to the composition enhanced the efficacy of polyvinyl alcohol in suspending hydrocortisone in aqueous preparations with ciprofloxacin hydrochloride and other components. See the ""930 patent at Col. 8, line 64-Col. 9, line 12.
The ""930 patent discloses a process for manufacturing compositions containing ciprofloxacin and hydrocortisone in Example 5 at Column 5, lines 27-67. According this manufacturing process, polyvinyl alcohol, lecithin, benzyl alcohol and acetic acid are sequentially added to prepare a first stock solution. Separately sodium chloride and sodium acetate are dissolved in water to form a second stock solution. A third stock solution is prepared by dissolving polysorbate 20 and dispersing hydrocortisone in water. Finally, ciprofloxacin is either added to the first stock solution or ciprofloxacin is prepared as a fourth stock solution by dissolving ciprofloxacin, acetic acid and sodium acetate to form a ciprofloxacin stock solution. After the first and second stock solutions are combined, the ciprofloxacin stock solution is added to the combined solution. Finally, the third stock solution polysorbate 20 and hydrocortisone is mixed with the remaining batch volume.
A suspension composition""s physical stability can be measured by two common methods. First, the resuspendability of a composition can be measured by allowing a homogeneous to remain standing in a cylindrical container for a period of time, then determining the number of inversions of the cylindrical container necessary to resuspend any sediment that form while the composition was standing. Second, the rate of settling can be measured by allowing a homogeneous suspension composition to remain standing for a period of time, then observing the height of sedimentation visible in a sample contained in a cylinder. Larger sedimentation heights indicate less separation with less supernatant liquid. Both measures of physical stability are important. A composition that is very easy to redisperse but that settles too quickly can be difficult to manufacture. Suspension compositions must remain well dispersed during processing and filling operations while commercial supplies are prepared in order to insure uniform products.
The present invention provides ciprofloxacin and hydrocortisone compositions that have excellent physical stability. The compositions are prepared by dispersing for greater than 45 minutes hydrocortisone with lecithin and optionally a polysorbate surfactant prior to combining hydrocortisone with the remainder of the composition. Among other factors, the present invention is based upon the finding that a specific order of addition of ingredients in compositions containing ciprofloxacin, hydrocortisone, a preservative, a non-ionic surfactant, a buffer, a tonicity agent, lecithin, polyvinyl alcohol and water can provide compositions with excellent physical stability. Compositions prepared by dispersing hydrocortisone with lecithin prior to mixing hydrocortisone with the balance of ingredients in the compositions have superior physical stability compared to those prepared by dispersing hydrocortisone with only a polysorbate surfactant prior to adding the hydrocortisone ingredient to the balance of the composition.
Unless otherwise indicated, all ingredient concentrations are listed as percent (w/w).
Ciprofloxacin is present in the compositions of the invention in an amount effective for anti-bacterial action. Such amounts range from about 0.01-1%, preferably from about 0.1-0.5%, and most preferably about 0.2%. Compositions of the present invention also comprise hydrocortisone as an anti-inflammatory agent. Hydrocortisone is present in an amount effective for anti-inflammatory action. Such amount typically ranges from about 0.1-3%, preferably about 0.1-2%, and most preferably about 1%. Particularly for ophthalmic use, small particle sizes are preferred. As used herein, xe2x80x9cmicronizedxe2x80x9d hydrocortisone means hydrocortisone particles having an average particle size xe2x89xa610 xcexcm (based on surface area (dsn)). If the particle size of the hydrocortisone raw material as received from the supplier is unsatisfactory, one or more known sizing techniques, such as ball milling or micronizing, can be used to adjust the particle size into the desired range.
To prevent contamination by microorganisms and provide a reasonable shelf-life, the compositions of the present invention include a preservative. Acceptable preservatives are required to cause no or insignificant ototoxicity, sensitization or irritation of the ear. Additionally, the preservative must be jointly soluble with ciprofloxacin in water over a pH range of approximately pH 3-6. The most preferred preservative is benzyl alcohol, which is typically present in an amount from about 0.1-3%, preferably about 0.1-2%, and most preferably about 0.9%.
A tonicity adjusting agent is preferably contained in an amount sufficient to cause the composition to be approximately isotonic, that is an amount effective to adjust the tonicity of the composition from about 150-800 mOsm, preferably 200-600 mOsm. A preferred tonicity-adjusting agent is sodium chloride.
A buffering agent is desirable for the compositions of the present invention. The preferred buffering system is an acetate buffer comprising acetic acid and sodium acetate. Amounts of sodium acetate and acetic acid effective to buffer the preparation in a pH range of about 4.0-5.3, preferably about 4.4-4.9 and most preferably about 4.7, range from about 0.1-3% of sodium acetate and from about 0.01-10% of acetic acid. Preferably the amount of sodium acetate is from about 0.1-2% and most preferably about 0.6-0.7%. Preferably the amount of sodium acid is about 0.1-5% and most preferably about 0.2-0.3%. Sodium acetate is preferably used in the form of sodium acetate trihydrate and acetic acid is preferably used in the form of glacial acetic acid.
To allow the compositions of the present invention to wet and spread on the skin surface at the site of infection or inflammation in the ear canal, a non-ionic surfactant is desirable. The surfactants known as polysorbates, in particular polysorbates 20 to 80, are preferred. Such polysorbates are commercially available under the tradename Tween from ICI Americas, Inc. Most preferred is polysorbate 20. The amount of polysorbate surfactant contained in the compositions of the present invention generally ranges from about 0.01-2%, preferably about 0.05-1%, and most preferably about 0.1%.
To help maintain or improve the physical stability of the suspension composition of the present invention, lecithin or a lecithin derivative is added. Lecithins from natural/vegetative (e.g., egg or soy lecithin) and synthetic origins are known. The primarily type of lecithin is phosphatidylcholine (PC). Other types of lecithins include phosphatidylglycerol; phosphatidylinositol; sphingomyelin; and phosphatidylethanolamine. Derivatives of lecithin with saturated and unsaturated fatty acid side chains on PC, are also known, including: distearoylphosphatidyl choline; dipalmitoylphosphatidyl choline; and dimirystoylphosphatidyl choline. As used herein, xe2x80x9clecithinxe2x80x9d includes such derivatives of lecithin. Preferably, the lecithin ingredient comprises at least 75% PC.
Commercially available grades of soy lecithins include a fully hydrogenated soy lecithin comprising 90% phosphatidylcholine available under the tradename Phospholipon 90H from American Lecithin Company and a soy lecithin comprising 75% phosphatidylcholine available under the tradename Lipoid-S75 from Vernon Walden, Inc. The amount of lecithin contained in the compositions of the present invention depends primarily on the concentration of insoluble ingredients in the compositions. The amount of lecithin in the compositions of the present invention generally ranges from about 0.01-5%, preferably about 0.01-2% and most preferably is about 0.15%.
In addition to the excipients mentioned above, the ciprofloxacin and hydrocortisone compositions of the present invention optionally comprise polyvinyl alcohol as a viscosity-augmenting agent. The polyvinyl alcohol contained in the composition of the present invention should be at least 85% hydrolyzed, with grades ranging from 85% hydrolyzed to 99+% hydrolyzed being suitable. Most preferred is an 88% hydrolyzed grade of polyvinyl alcohol, such as that commercially available as Airvol 205S from Air Products and Chemicals, Inc. The amount of polyvinyl alcohol ingredient in the compositions of the present invention is preferably an amount effective to cause the composition to have a viscosity ranging from about 2-8 cps (when measured at room temperature using a Brookfield Viscometer set at 30 rpm and a CP 42 spindle). Preferably, the polyvinyl alcohol ingredient is present in an amount sufficient to cause the composition""s viscosity to be from about 3-7 cps.
The compositions of the present invention are prepared in a specific manner. It is essential that the hydrocortisone ingredient is first mixed with lecithin for greater than 45 minutes prior to combining the hydrocortisone ingredient with the remainder of the composition. Preferably, hydrocortisone is mixed with both lecithin and a polysorbate 20 to 80 surfactant before combining hydrocortisone with the remainder of the composition. The presence of the polysorbate surfactant provides a lower viscosity slurry than simply mixing hydrocortisone and lecithin alone. The lower viscosity achieved by the addition of the polysorbate surfactant makes processing easier.
As mentioned above, hydrocortisone is preferably sized to achieve desirable particle sizes. The hydrocortisone ingredient in the compositions of the present invention can be sized in the presence of lecithin and optionally a polysorbate 20 to 80 surfactant. If the hydrocortisone ingredient is sized prior to mixing with lecithin, then the mixing with lecithin step must occur prior to combining hydrocortisone with the remainder of the ciprofloxacin and hydrocortisone composition. Particle sizing techniques are known in the art and include ball milling, homogenization and micronization. As used herein, xe2x80x9cmixingxe2x80x9d includes simple mixing as well as sizing procedures.
The lecithin ingredient should be dispersed in water at a temperature above the phase transition temperature for the chosen grade of lecithin. In the case of phospholipon 90H, the phase transition temperature is approximately 51xc2x0 C. Therefore, Phospholipon 90H is preferably dispersed at a temperature of approximately 65-70xc2x0 C. A polysorbate surfactant, if present, can be dispersed simultaneously with lecithin or added before or after lecithin is fully dispersed. After the polysorbate surfactant and lecithin are dispersed, hydrocortisone (preferably micronized) is then dispersed. The hydrocortisone is preferably added after removing the lecithin dispersion from heat, but before the lecithin dispersion cools to room temperature. The hydrocortisone ingredient is preferably mixed with the lecithin dispersion for approximately 6 to 18 hours or more, and most preferably about 12 hours, before being added to the remainder of the ciprofloxacin/hydrocortisone composition.
In a separate vessel, ciprofloxacin is dissolved in water with an acetate buffer, then the benzyl alcohol preservative, sodium chloride tonicity adjusting agent and the polyvinyl alcohol viscosity augmenter are sequentially added, with each ingredient being dispersed or dissolved prior to the addition of the next. Although it is possible to add all of these ingredients simultaneously rather than sequentially provided that the vessel contains a sufficient amount of water, sequentially mixing and dispersing is preferred.
After the ciprofloxacin solution has been prepared, it is combined with the hydrocortisone slurry then the pH is adjusted with NaOH or HCl and the batch volume is adjusted with purified water.
The ciprofloxacin/hydrocortisone compositions described above are preferably prepared as follows.
1. Add approx. 5-50% of the total batch volume of purified water to a compounding vessel and heat to a temperature above the transition temperature of the chosen grade of lecithin (in the case of Phospholipon 90H the preferred temperature is approximately 65-70xc2x0 C.).
2. Using a magnetic stir bar, disperse 50% of the total required amount of lecithin (preferably, Phospholipon 90H) and 50% of the total required amount of surfactant (preferably polysorbate 20) into the heated water of Step 1 until uniformly dispersed (generally about 10-20 min.). Remove from heat.
3. Add the hydrocortisone (preferably micronized hydrocortisone) before the dispersion of Step 2 cools to room temperature and mix for approximately 12 hrs. (i.e., overnight).
4. Prepare a ciprofloxacin solution by adding the following components in order and mix well allowing each to disperse or dissolve before adding the next: the remaining 50% of the total amount of lecithin (at elevated temperature), the remaining 50% of the total amount of surfactant, the preservative, the buffer (e.g., glacial acetic acid then sodium acetate (trihydrate)), ciprofloxacin, and the tonicity-adjusting agent, and optionally polyvinyl alcohol (from stock solution).
5. Prepare a stock solution of polyvinyl alcohol in purified water. The stock solution is preferably prepared at a polyvinyl alcohol concentration of about 0.5 or 1.0% and preferably prepared at 90-95xc2x0 C. (for easier and faster solution preparation) then cooled to room temperature.
6. Add the hydrocortisone dispersion of Step 3 to the ciprofloxacin solution of Step 4 (while mixing), then mix in the required amount of polyvinyl alcohol stock solution.
7. QS to 90% with purified water
8. Measure and adjust pH to about 4.7 with 1N NaOH and/or 1N HCl, then QS to 100% with purified water.